The changing face of sympathetic overactivity in hypertension

There is a lot of evidence showing that sympathetic activity is increased in a large proportion of patients with hypertension. However, the clinical impact of this state is frequently underestimated. Several factors seem to be misunderstood, such as whether sympathetic overactivity is reproducibly present, whether it lasts throughout 24 h, and what is the significance of its association with tachycardia. In this review, we present data to indicate that several haemodynamic changes in hypertension such as elevated cardiac output and heart rate and alteration in vascular resistance are neurogenic. The relationship between the increased sympathetic tone and decreased parasympathetic tone in hypertension is reciprocal, which strongly suggests that the abnormality emanates from the brain. The increase in sympathetic drive in hypertension is widespread across many organs. Beside the heart it is seen in the kidney and skeletal muscle, and even in platelets. We also discuss the possible mechanisms of the haemodynamic transition from this hyperkinetic state to established hypertension. We propose a hypothesis where down-regulation of beta-adrenergic responsiveness plays a major role in explaining the haemodynamic changes as well as metabolic alterations, such as hyperinsulinaemia and even the gain of weight in hypertension. Thus, the increased sympathetic tone may be involved in the genesis of multiple, pressure-independent coronary risk factors in hypertension.     

The meaning of dopamine beta-hydroxylase in essential hypertension.

1. Resting plasma dopamine beta-hydroxylase (DBH) activity and haemodynamic parameters were studied in untreated borderline (twenty-nine) and permanent (twenty-seven) essential hypertensive patients. DBH was also measured in sixty-three apparently healthy subjects. 2. Mean DBH values were not significantly different between the groups. 3. Cardiac output, cardiopulmonary blood volume and the cardiopulmonary blood volume/total blood volume ratio (CPBV/TBV) were significantly higher in borderline than in permanent hypertensive patients. 4. In borderline hypertensive patients, plasma DBH activity was directly correlated with diastolic arterial pressure and with values of cardiac output, cardiopulmonary blood volume and CPBV/TBV ratio. No such correlations could be observed in the permanent hypertensive group. 5. These results suggest that plasma DBH activities in borderline hypertension mainly depend on the sympathetic activity responsible for the haemodynamic variations. Contrariwise, plasma DBH activities in permanent essential hypertensive patients appear to reflect other factors.     

Pathophysiology of essential hypertension: an update

ABSTRACT

Introduction: Hypertension is caused by increased cardiac output and/or increased peripheral resistance.

Areas covered: The various mechanisms affecting cardiac output/peripheral resistance involved in the development of essential hypertension are covered. These include genetics; sympathetic nervous system overactivity; renal mechanisms: excess sodium intake and pressure natriuresis; vascular mechanisms: endothelial cell dysfunction and the nitric oxide pathway; hormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS); obesity, obstructive sleep apnea (OSA); insulin resistance and metabolic syndrome; uric acid; vitamin D; gender differences; racial, ethnic, and environmental factors; increased left ventricular ejection force and hypertension and its association with increased basal sympathetic activity – cortical connections.

Expert commentary: Maximum association of hypertension is found with sympathetic overactivity which is directly or indirectly involved in different mechanisms of hypertension including RAAS, OSA, obesity, etc.. It is not overt sympathetic activity but disturbed basal sympathetic tone. Basal sympathetic tone arises from hypothalamus; possibly affected by cortical influences. Therefore, hypertension is not merely a disease of circulatory system alone. Its pathogenesis involves alteration in ANS (autonomic nervous system) and likely in cortical-hypothalamic connections. Assessment of ANS and cortical-hypothalamic connections may be required for better understanding of hypertension.     

Abnormalities in the regulation of sympathetic activity in human hypertension

Various biochemical, pharmacologic, and physiologic techniques were used to evaluate the sympathetic tone and reactivity in labile and sustained hypertension in humans. The results of these studies suggest the existence of an important subgroup of hypertensive patients characterized by increased basal sympathetic tone and reactivity to standing. Such abnormalities could be the result of various dysfunctions, involving the activity of central and peripheral cardiovascular sympathetic fibers, the presynaptic modulation of sympathetic fibers (including the interaction with the parasympathetic system), the inactivation of circulating norepinephrine, and the sensitivity of the efferent cells. The increase in circulating norepinephrine in a group of hypertensive patients seems to reflect a functional increase in the sympathetic tone as shown by the presence of hyperkinetic cardiac functions in hyperadrenergic patients (elevated catecholamine levels), while cardiac functions are normal in normoadrenergic patients (catecholamine levels within normal range). Moreover, the better hypotensive response, combined with normalization of the basal and reactive circulating norepinephrine levels following beta-blockade in hyperadrenergic hypertensive patients, strongly supports the participation of the sympathetic system in the maintenance of hypertension in those patients. The identification and characterization of this subpopulation of patients may be helpful in the development of more rational therapeutic approaches and could eventually permit us to devise better predictors of outcome in hypertension.     

Hemodynamic effects of antihypertensive drugs

Elevated total peripheral resistance and normal cardiac output are the hemodynamic characteristics of chronic essential hypertension. One approach to treating hypertension matches the individual pathophysiology with the hemodynamic effects of antihypertensive drugs. Antiadrenergic drugs are appropriate second-step therapy in many cases of established hypertension; by reducing total peripheral resistance, these agents can reduce blood pressure while sparing cardiac output and renal blood flow. The physician should treat elderly hypertensive patients cautiously and consider using drug with a favorable hemodynamic profile.     

Essential hypertension: neural considerations

Current evidence suggests that the sympathetic nervous system plays a predominant role in some fraction of essential hypertension. Patients in whom such mechanisms are likely to be operative are young people with mild or labile hypertension. These mechanisms are expressed clinically through orthostatic hypertension, rapid heart rate, modestly elevated cardiac output, and normal or slightly elevated peripheral vascular resistance. The vascular resistance is inappropriately high for the level of cardiac output, and this is reflected in a mildly elevated blood pressure. This evidence carries therapeutic implications and suggests that sympatholytic drugs should be the first line of therapy. An additional pressor mechanism may arise from increased sympathetic activity along renal efferent nerves that impairs sodium excretion and another possible mechanism is stimulation of brain centers through impulses from the kidneys carried in renal afferent nerves.     

The mechanisms regulating pulse-wave spreading time in a biological feedback regimen in patients with borderline arterial hypertension and in healthy subjects

The regulatory mechanisms of pulse transit time (PTT) during biofeedback training were studied by noninvasive cardiovascular monitoring in borderline hypertensive and normotensive subjects. Hemodynamic parameters were used as indirect indices of autonomous nervous system activity. All the patients were capable of increasing PTT. Systolic blood pressure demonstrated significant correlation with PTT. The effects were mediated by the different combinations of sympathetic and parasympathetic drives. In the initial 5 sessions, there was the most significant decrement of sympathetic, especially beta-adrenergic activity, expressed in the reduction of the myocardial contractility and cardiac output. In the retraining period (6 to 12 sessions), the leading role was played by the reduction of the arterial tone and total peripheral resistance. Respiratory arrhythmia rose in both cases as a result of the increased parasympathetic activity.     

The cyclicity of changes in the autonomic regulation of the hemodynamics and the effects of clofelin in women with hypertension]

As many as 56 healthy women and 45 women of reproductive age, suffering from essential hypertension (EH) were examined for the effect of ovarian cycle phases on vegetative regulation of central hemodynamics and pharmacodynamic effects of hemiton. The healthy persons in the phase of proliferation (I) and secretion (III) demonstrated the predominance of the parasympathetic tone and high responsiveness of the autonomic nervous system (ANS). The phase of ovulation (II) and the menstrual phase (IV) were characterized by the high sympathetic tone and low responsiveness of both parts of the ANS. The lowest values of the stroke and minute blood volumes were detected in phase II, whereas the highest ones in phase IV. In EH patients, the recurrence of ANS function was disturbed, the dynamics of the parameters became opposite to that seen in healthy persons. Hemiton produced the maximal hypotensive effect in phases I and II, the minimal one in phases III and IV. In phases I and III, the drug minimized the cardiac output; the general peripheral resistance was reduced in phases I and II; in phase IV, the drug did not provoke any significant changes in hemodynamics. The data obtained permit a differentiated approach to the distribution of the hemiton dose required for the treatment course in EH women of reproductive age.     

Arterial distensibility in young normotensive subjects and in patients with borderline and essential hypertension

We evaluated the indices of arterial distensibility in a group (N = 40) of normotensive subjects and patients with borderline or established hypertension by measuring intra-arterial pressure, pulse wave velocity, and a mathematical modification of MOEN's formula to calculate arterial distensibility. Multiple linear regression analysis including six hemodynamic variables (systolic pressure [SP], diastolic pressure, mean arterial pressure, cardiac output, stroke volume, total peripheral resistance) and age showed that SP and age are the best predictor indices for arterial distensibility (P less than .025; both inversely correlated with arterial distensibility) and for pulse wave velocity (P less than .001; both positively correlated with pulse wave velocity). Patients aged 48 years and under (N = 35) with no evidence of target organ damage showed significant differences in arterial distensibility (F = 5.41; P less than .01) among normal, borderline, and established hypertensive subjects; arterial distensibility was lower in those with borderline (P less than .025) and established hypertension (P less than .01) when compared with the normal group. We concluded that arterial distensibility is decreased in borderline as well as in established essential hypertension without target organ involvement and that age and systolic pressure are the best predictors of arterial distensibility.     

Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects

The risk of cardiovascular disease has been linked to sympathetic activation and its incidence is known to be lower in women than in men. However, the effect of gender on the sympathetic vasoconstrictor drive has not yet been established. In the present study, we investigated whether there is a gender difference in MSNA (muscle sympathetic nerve activity) and blood flow, and to determine the mechanisms involved. We examined 68 normal subjects, 34 women and 34 men, matched for age, BMI (body mass index) and waist circumference. MSNA was measured as the mean frequency of single units (s-MSNA) and as multi-unit bursts (m-MSNA) from the peroneal nerve simultaneously with its supplied muscle CBF (calf blood flow). Women had lower (P=0.0007) s-MSNA (24+/-2.0 impulses/100 cardiac beats) than men (34+/-2.3 impulses/100 cardiac beats), and a greater baroreceptor reflex sensitivity controlling efferent sympathetic nerve activity than men. The sympathetic activity was inversely and directly correlated respectively, with CBF (P=0.03) and CVR (calf vascular resistance; P=0.01) in men only. The responses of an increase in CVR to cold pressor and isometric handgrip tests were significantly smaller in women (P=0.002) than in men, despite similar increases in efferent sympathetic nerve activity. Women had a lower central sympathetic neural output to the periphery, the mechanism of which involved differences in central and reflex control, as well as a lower vasoconstrictor response to this neural output. It is suggested that this may partly explain the observed lower incidence of cardiovascular events in women compared with men.     

Renal haemodynamics before and after splanchnic block in patients with hypertension

In eighteen patients with hypertension of presumed renal origin the haemodynamics of the kidney were studied by arterial pressure recording, blood flow measurement and selective arteriography before and after a splanchnic block. The material was divided into kidneys with and kidneys without arterial stenosis. In these patients with hypertension a positive correlation was found between mean arterial pressure and renal vascular resistance both before and after the splanchnic block. In patients with renal arterial stenosis the change in relative renal vascular resistance was negatively correlated to the initial resistance, implying that in kidneys with a high initial vascular resistance the resistance decreased to a relatively greater extent than in kidneys with a low initial resistance. At high blood pressures ischaemic areas in the kidney were found. The volume of these areas is dependent upon sympathetic tone, such that a high sympathetic tone results in ischaemia of a larger volume of the kidney. This applies both to kidneys with and to those without arterial stenosis. The results of this investigation thus support the assumption that in the presence of hypertension a kidney is under the control of a sympathetic tone that may form a part of the pathogenetic process in hypertension.     

Hyperinsulinemia or increased sympathetic drive as links for obesity and hypertension

The association of obesity with hypertension has been amply demonstrated in cross-sectional, longitudinal, and dietary-intervention studies, but the mechanisms remain enigmatic. Both conditions are independently characterized by similar metabolic alterations, i.e., glucose intolerance, dyslipoproteinemia, elevated serum uric acid, and inadequate Na+ transport. Obesity, hypertension, and these metabolic alterations are associated with hyperinsulinemia/insulin resistance. The degree of these alterations is lowest in lean hypertensives, intermediate in obese normotensives, and greatest in obese hypertensives, but mortality risk is highest in lean hypertensives. This apparent discrepancy may be related to the divergent hemodynamic characteristics, possibly indicating different etiology, of lean and obese hypertensives, i.e., contracted blood volume, increased total vascular peripheral resistance, and normal sympathetic drive in the former, expanded blood volume, normal peripheral resistance, and increased sympathetic drive in the latter. Current knowledge suggests that the interrelationships of obesity and hypertension with the metabolic alterations could be mediated by high carbohydrate and fat consumption and low physical activity, resulting in obesity and separate pathways in hyperinsulinemia and increased sympathetic drive, leading to a double vicious cycle. In one, hyperinsulinemia and the consequent insulin resistance would compound one another. In the second, the increasing hyperinsulinemia would increasingly stimulate the sympathetic nervous system. This double vicious cycle could result in increasing hemodynamic and metabolic derangements causing hypertension, diabetes, and atherosclerotic cardiovascular disease (ASCVD). The association of lean hypertension with ASCVD may be through other mechanisms, e.g., hemodynamic forces on the vascular endothelium.     

Hydrochlorothiazide-induced sympathetic hyperactivity in hypertensive patients.

Hydrochlorothiazide-induced diuresis and natriuresis is considered to be responsible for the antihypertensive effect of this drug. After short-term treatment there is decreased cardiac output and increased peripheral resistance which we have found to be attended by increased plasma norepinephrine (NE) levels. After longer treatment cardiac output returns to normal and peripheral resistance declines. At this time, plasma NE levels remain elevated, indicating that peripheral resistance reduction is not a consequence of a reduction of the elevated level of sympathetic activity. These results provide a rationale for the combined use of diuretics and drugs which diminish noradrenergic activity in the treatment of hypertension.     

Effects of antihypertensive therapy on the hemodynamics of hypertension: clinical implications

Early essential hypertension is characterized by high cardiac output and normal total peripheral resistance and renal blood flow; in chronic hypertension, total peripheral resistance is elevated, cardiac output is decreased from initial levels, and renal blood flow diminishes as the disease progresses. The various classes of antihypertensive drugs induce different hemodynamic effects to maintain blood pressure control. Long-term administration of all classes of antihypertensive drugs results in a decrease in mean arterial pressure, and most drugs reduce total peripheral resistance. Heart rate and cardiac output generally remain unchanged, but they are decreased after long-term therapy with beta-blockers. Some beta-blockers also reduce renal blood flow. Drugs such as the selective alpha 1-adrenergic blocking agent prazosin, which normalizes the hemodynamic profile of hypertension, appear to be advantageous. In addition, prazosin maintains exercise tolerance at near-normal levels.     

Obesity hypertension

Obesity and hypertension are two major risk factors for the cardiovascular system. Whereas arterial hypertension increases afterload to the left ventricle, obesity produces an increase in stroke volume and increases preload. As a result of this double burden, the heart adapts with eccentric left ventricular hypertrophy. Contractility becomes impaired early in the course of obesity hypertension, and ventricular ectopy is observed. As a consequence, the obese hypertensive patient is at a high risk for congestive heart failure and sudden death. Despite the synergistic effects of obesity and hypertension on the heart, patients appear to be relatively protected from nephrosclerosis and coronary artery disease. These epidemiologic observations are supported by the pathophysiologic changes that take place in obesity hypertension. At any given level of arterial pressure, cardiac output and renal blood flow are elevated in obese hypertensive patients, whereas systemic and renal vascular resistance are decreased when compared to lean hypertensive patients. Because total peripheral resistance is considered the hemodynamic hallmark of arterial hypertension, systemic vascular complications may be less pronounced in obesity hypertension. Weight loss decreases preload, afterload to the left ventricle, and the sympathetic drive to the heart. Protecting the heart from these hypertrophic stimuli should be a major goal of preventive cardiology.     

Cardiac contractility,central haemodynamics and blood pressure regulation during semistarvation

Eight obese patients were studied before and after 2 weeks of treatment by a very-low-calorie diet (VLCD). Cardiac output and central blood volume (pulmonary blood volume and left atrial volume) were determined by indicator dilution (¹²⁵I-albumin) and radionuclide angiocardiography (first pass and equilibrium technique by [⁹⁹Tc^m]red blood cells). Cardiac output decreased concomitantly with the reduction in oxygen uptake as the calculated systemic arteriovenous difference of oxygen was unaltered. There were no significant decreases in left ventricular contractility indices, i.e. the ejection fraction, the peak ejection rate and changes in end-systolic volume. Also the diastolic function evaluated by the peak filling rate remained normal. Furthermore, no sign of backward failure could be demonstrated since the central blood volume was not significantly increased. Both systolic and diastolic blood pressure (BP) declined. The fall in BP was caused by the reduction in cardiac output as the total peripheral resistance was unchanged. Finally, the decline in total blood volume was not significant. These findings together with a reduction in heart rate indicated that a reduced sympathetic tone via increased capacitance of the venous bed was the main operator of a reduced venous return. Thus, the haemodynamic alterations in obese patients during short-term semistarvation may be caused by the fall in oxygen uptake and produced mainly by changes in the sympathetic tone.     

Autonomic control of the venous system in health and disease: effects of drugs

The venous system contains 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an ₁- or ₂-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An ₁- or ₂-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several -adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.     

Hemodynamic and sympathetic nervous system responses to stress during the menstrual cycle

In this study, the impact of menstrual cycle phase on hemodynamic and sympathetic nervous system responses was examined during exposure to a battery of laboratory stressors. Participants were 40 healthy premenopausal women, aged 26 to 51. Impedance cardiography was used to measure stroke volume, heart rate, and cardiac output. Systemic vascular resistance was derived on the basis of concurrently recorded blood pressure and cardiac output. The menstrual cycle's effect on the sympathetic nervous system response was explored by evaluating plasma catecholamine responses during stress. In luteal compared with follicular subjects, systemic vascular resistance was significantly lower during all stress tasks (P < 0.03). Catecholamine responses were also significantly lower in luteal subjects (P < 0.004). The results suggest that the sympathetic nervous system may respond to stress differently during different phases of the menstrual cycle. This finding has implications for understanding "whitecoat hypertension" in women, and highlights the need to measure blood pressure during several office visits. Perhaps high blood pressure readings recorded during the follicular phase should be reexamined during the luteal phase before considering pharmacologic intervention.     

The right ventricle: interaction with the pulmonary circulation

The primary role of the right ventricle (RV) is to deliver all the blood it receives per beat into the pulmonary circulation without causing right atrial pressure to rise. To the extent that it also does not impede left ventricular (LV) filling, cardiac output responsiveness to increased metabolic demand is optimized. Since cardiac output is a function of metabolic demand of the body, during stress and exercise states the flow to the RV can vary widely. Also, instantaneous venous return varies widely for a constant cardiac output as ventilatory efforts alter the dynamic pressure gradient for venous return. Normally, blood flow varies with minimal changes in pulmonary arterial pressure. Similarly, RV filling normally occurs with minimal increases in right atrial pressure. When pulmonary vascular reserve is compromised RV ejection may also be compromised, increasing right atrial pressure and limiting maximal cardiac output. Acute increases in RV outflow resistance, as may occur with acute pulmonary embolism, will cause acute RV dilation and, by ventricular interdependence, markedly decreased LV diastolic compliance, rapidly spiraling to acute cardiogenic shock and death. Treatments include reversing the causes of pulmonary hypertension and sustaining mean arterial pressure higher than pulmonary artery pressure to maximal RV coronary blood flow. Chronic pulmonary hypertension induces progressive RV hypertrophy to match RV contractility to the increased pulmonary arterial elastance. Once fully developed, RV hypertrophy is associated with a sustained increase in right atrial pressure, impaired LV filling, and decreased exercise tolerance. Treatment focuses on pharmacologic therapies to selectively reduce pulmonary vasomotor tone and diuretics to minimize excessive RV dilation. Owning to the irreversible nature of most forms of pulmonary hypertension, when the pulmonary arterial elastance greatly exceeds the adaptive increase in RV systolic elastance, due to RV dilation, progressive pulmonary vascular obliteration, or both, end stage cor pulmonale ensues. If associated with cardiogenic shock, it can effectively be treated only by artificial ventricular support or lung transplantation. Knowing how the RV adapts to these stresses, its sign posts, and treatment options will greatly improve the bedside clinician’s ability to diagnose and treat RV dysfunction.